1. Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study.
- Author
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Whittaker A, Kragh ÅM, Hartleib-Geschwindner J, Albayaty M, Backlund A, Greasley PJ, Heijer M, Kjaer M, Forte P, Unwin R, Wernevik L, and Ericsson H
- Subjects
- Administration, Oral, Adolescent, Adult, Aldosterone blood, Aldosterone metabolism, Area Under Curve, Benzoates administration & dosage, Benzoates pharmacokinetics, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Half-Life, Healthy Volunteers, Heart Failure blood, Heart Failure drug therapy, Heart Failure etiology, Humans, Hyperkalemia blood, Hyperkalemia chemically induced, Hyperkalemia diagnosis, Male, Middle Aged, Mineralocorticoid Receptor Antagonists administration & dosage, Mineralocorticoid Receptor Antagonists pharmacokinetics, Oxazines administration & dosage, Oxazines pharmacokinetics, Potassium blood, Renal Elimination, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic drug therapy, Renal Insufficiency, Chronic etiology, Risk Assessment statistics & numerical data, Young Adult, Benzoates adverse effects, Hyperkalemia epidemiology, Mineralocorticoid Receptor Antagonists adverse effects, Oxazines adverse effects, Receptors, Mineralocorticoid metabolism
- Abstract
Excessive activation of the mineralocorticoid receptor (MR) underlies the pathophysiology of heart failure and chronic kidney disease. Hyperkalemia risk limits the therapeutic use of conventional MR antagonists. AZD9977 is a nonsteroidal, selective MR modulator that may protect nonepithelial tissues without disturbing electrolyte balance. This phase I study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of AZD9977 in healthy volunteers. Twenty-seven male participants aged 23-45 years were randomized 3:1 to receive oral AZD9977 or placebo for 8 days (with twice-daily dosing on days 2-7), in dose cohorts of 50, 150, and 300 mg (AZD9977, n = 6 per cohort; placebo, n = 3 per cohort). Adverse events occurred in 4 of 18 participants receiving AZD9977 (22.2%) and 6 of 9 receiving placebo (66.7%), all of mild or moderate severity; none were serious or led to withdrawal. AZD9977 was rapidly absorbed, with median time of maximum concentration of 0.50-0.84 hours across dose groups. Area under the curve and maximum concentration were approximately dose proportional but elimination and accumulation terminal half-life increased with dose. Steady-state was reached after 3-4 days, with dose-dependent accumulation of 1.2-1.7-fold. Renal clearance was 5.9-6.5 L/hour and 24-37% of AZD9977 was excreted in the urine. Serum aldosterone levels increased dose dependently from days -1 to 7 in participants receiving AZD9977, but serum potassium levels and urinary electrolyte excretion were unchanged. AZD9977 was generally well-tolerated with no safety concerns. Exploratory outcomes suggested reduced hyperkalemia risk compared with MR antagonists. These findings support further clinical development of AZD9977., (© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2020
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